Peripheral nerve cells regenerate after an injury, but recovery of function is only observed in some patients. One reason for this is a lack of axon regeneration (see following figure, a) or faulty innervation of target structures (b). The latter is often observed in branching axons (i.e. axon collaterals) that reach the "wrong" targets during peripheral nerve regeneration. In the case of the motor neuron shown here, this can be the skin normally innervated by sensory nerves or an inappropriate muscle. If it is an antagonist of the originally innervated muscle, it will counteract the intended movement (Fig. 1.19 from Klimaschewski LP, Die Regeneration von Nerven und Rückenmark: Was wir über Mechanismen und therapeutische Ansätze wissen, Springer 2023).
However, previous studies in mammals have described "preferential motor reinnervation" (PMR), which suggests a tendency of motor neurons to regenerate in the direction of the muscle nerve branch rather than the cutaneous branch. This phenomenon has been repeatedly questioned in the field and appears to depend on many factors such as the type of animal or the exact method of repair.
On the other hand, correct reinnervation of sensitive target structures would also be relevant in order to enable not only movements but also specific sensations such as pain, temperature or touch after peripheral nerve regeneration. Previous studies have indicated that sensitive axons can preferentially regrow via the cutaneous branch after a lesion. In addition, the muscle afferents necessary for proprioceptive input appear to show a preference for the motor nerve branch. In order to test these hypotheses, Esther Udina from the institute of the well-known regeneration researcher Xavier Navarro in Barcelona has now examined special reporter mice that produce fluorescent proteins in functionally defined nerve cells.
The genetic labeling of these neurons makes it possible to recognize a possible preference for axonal regeneration in different neuron types and to quantify collateral axonal branching. To this end, she severed the femoral nerve of the mice above the bifurcation into its two main branches and repaired them with fibrin glue. One and eight weeks after the lesion, retrograde neuronal labeling was achieved by application of tracers to the distal branches of the nerve and the marked cell bodies and axons were counted in the motor and sensory nerve branches, respectively.
This experimental approach made it possible to investigate the specificity of motor neurons and of two sensory nerve cell populations that have different target organs: the proprioceptors, which innervate muscle spindles, and cutaneous mechanoreceptors, whose endings are mainly located in the skin. It was found that the cutaneous mechanoreceptors regenerated faster than motor neurons and proprioceptors. Furthermore, there must be a mechanism that directs peripheral axons of all qualities towards a sensory nerve branch shortly after the injury. In the long term, it was observed that motor neurons and proprioceptors prefer the muscle branch of a regenerating nerve, while the cutaneous mechanoreceptors were primarily detectable in the sensory nerve branch. It was also striking that myelinated neurons with thick axons form more axon collaterals in the cutaneous than in the muscular branch of the femoral nerve, and that motor neurons have more collaterals than proprioceptors.
Thus, the classical concept of PMR needs to be extended to sensory neurons. Since the specificity observed is only detectable after many weeks, both motor and sensory axon collaterals that do not regenerate into the "correct" target area are apparently withdrawn. It is possible that the differences in the regeneration dynamics and specificity of different neuron populations can be used therapeutically in the future to achieve functional recovery after nerve lesions in most patients (and not just a few).
Reference:
BolÃvar S, Udina E (2022) Preferential regeneration and collateral dynamics of motor and sensory neurons after nerve injury in mice. Experimental Neurology 358:114227
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